More than 10% of pregnancies now end in preterm birth. Many survivors face a lifetime of severe disabilities, and even those born only moderately early are at increased risk of consequences ranging from behavioral problems to chronic disease. Reducing both short- and long-term consequences of prematurity is thus critical to public health. However, too little is currently known about the etiology of disabling neonatal consequences of prematurity and about how preterm birth leads to lifelong behavioral and physical health problems. Our proposal addresses this barrier through three specific aims. In Aim 1, we will use computational methods to identify gene sets linking neonatal prematurity complications to later-onset disease. Significant and unexpected connections identified in this way generate testable hypotheses about the underlying causes of increased disease risks in individuals born preterm. For Aim 2, we will identify the molecular pathways leading to several neonatal prematurity complications, and we will assess previously-published theories about common causative pathways. In particular, we will determine whether there is a common inflammatory pathway or developmental deficiency leading to multiple complications. This will include developing a temporal profile of gene expression in preterm infants without complications and identifying any pathways where disrupted developmental profiles correlate with complications. Such patterns serve as further hypotheses whose causative role we can investigate. Finally, in Aim 3, we will experimentally test our new hypotheses by evaluating their ability to predict both short- and long-term outcomes. We will collect cord blood expression data from infants born at Tufts Medical Center, and we will assess the degree to which using the genes and pathways identified in Aims 1 and 2 improves our ability to predict outcomes for these infants during their hospital stays. To evaluate the connections with long-term outcomes proposed in Aim 1, we will assess the frequency of these consequences in children and adults born prematurely. The successful completion of this project will lead to better management of prematurity complications, to better understanding their long-term consequences, and potentially to new therapeutic approaches to prevent lifelong disabilities resulting from preterm birth.